The etiology of primary biliary cirrhosis (PBC) remains enigmatic despite significant advances in our understanding of the nature of the autoantigens and of the immune response. Based upon our pilot data, we submit that exposure to xenobiotics induces PBC in genetically susceptible hosts. This work is based on our previous observations that the immunodominant autoepitope for B cells, as well as autoreactive CD4 and CD8 cells, are all restricted to the inner lipoyl domain, highlighting this domain as a common hapten. Based upon this common lipoyl domain, we synthesized a library of synthetic structures designed to mimic a xenobiotic-modified lipoyl hapten that were then conjugated to the immunodominant PDC-E2 peptide. Using these structures, we determined that PBC sera were significantly more reactive against some hapten modified peptides than to the native lipoylated peptide. Furthermore, we have now demonstrated that immunization of rabbits and guinea pigs with one such xenobiotic compound, coupled to a large carrier (BSA), generates an AMA response which reacts with selfPDC-E2, binds to the inner lipoyl domain, and inhibits PDC-E2 function, thus recapitulating all the features of human AMA. We believe that this data provides solid evidence that a chemical xenobiotic conjugated to a protein that shares a motif with the autoantigen, may break tolerance, induce AMA, and ultimately lead to PBC. To prove this thesis, we need to perform a focused quantitative structure activity relationship analysis (QSAR) over a range of compounds to optimally define the structure that will best react with AMA. In addition, we need to significantly extend our study in rabbits and guinea pigs to define the spectrum of the immune response and induce immunopathology. We submit that a) additional QSAR studies may lead to a better understanding of the structure function relationships between the compound that breaks tolerance and the autoantibodies elicited by such a component, and thus may narrow our choice of compounds that are the true inducers of PBC; b) it may take a long time for animals immunized with the xenobiotic-carrier to develop disease (chronicity required); and c) that regardless of the identification of such compounds, disease induction and/or kinetics may need an additional immunological insult such as an inappropriate or Th1 cytokine environment. These studies are also critical for determining whether the immune response alone is essential for disease induction, or whether the unique milieu of human liver is required.